Preventing 2 viral infections with 1 tablet
Authors: Yi-Chia Huang, Chien-Ching Hung
Journal: Hepatology (2023)

Tenofovir (TFV), in the formulation of tenofovir disoproxil fumarate (TDF), has been the mainstay component of combination antiretroviral therapy (ART) since it received approval for HIV in 2001 and for chronic hepatitis B in 2008; and shortly thereafter, tenofovir alafenamide fumarate (TAF) was approved for the treatment of HIV and HBV infection in 2016. Guidelines have recommended TFV-based ART as the first-line therapy for people living with HIV (PLWH) who are coinfected with HBV. Other than for the treatment of HIV infection, coformulated TDF (300 mg) and emtricitabine (FTC, 200 mg) (TDF/FTC) was also approved for pre-exposure prophylaxis (PrEP) by the US FDA in 2012, with efficacy ranging from 44% to 100% in preventing HIV infection.1 Two oral dosing regimens are available for PrEP in preventing HIV infection: daily and on-demand oral PrEP with “2-1-1” dosing of TDF/FTC. Daily oral dosing of TDF/FTC for heterosexual men and women provides a stable plasma concentration after a 7-day lead-in duration for adequate tissue concentration to be achieved, whereas on-demand PrEP for men who have sex with men (MSM) requires taking 2 pills of TDF/FTC 2–24 hours before having sex and followed by 1 pill 24 hours and 48 hours, respectively, after the initial dosing.1 The rollout of PrEP with TDF/FTC, along with the early initiation of ART for all people living with HIV (PLWH), has become the major elements of the US initiative in ending the HIV epidemic over the past decade.1 Other countries committed to achieving the goal of ending the HIV epidemic have expanded health care services to improve access to HIV testing and PrEP for high-risk individuals. In the real-world setting, population-level impacts have been observed in regions or countries with a high PrEP coverage; for example, new HIV diagnoses have declined by 25% in the UK, 35% in New South Wales and Australia, and 58% in San Francisco. Moreover, with the widespread use of ART and increasing implementation of PrEP programs, the global HIV incidence has declined among adolescents and young adults between 1990 and 2019.2 Implementation of PrEP in preventing HIV infection, however, has raised concerns about an increasing incidence of sexually transmitted infections (STIs) among PrEP users due to the increases in condomless sex, number of sexual partners, or other high-risk behaviors. A meta-analysis including 88 studies from 26 countries estimated a strikingly high STI incidence of 72.2 per 100 person-years follow-up (95% CI, 60.5-86.2 per 100 person-years follow-up) among PrEP users.3 The most commonly described STIs included chlamydia, gonorrhea, and early syphilis at different anatomical sites.3 Although the increasing incidence of STIs among PrEP users could also be attributed to the increased case finding and diagnoses due to improved accessibility to testing at the PrEP services, a recent cohort study that analyzed the rates of STIs before and after the PrEP rollout in Australia suggested a continuously increasing trend without exaggeration by PrEP programs among MSM at high risk.4 The highest incidence rates of STIs occurred in the early months of PrEP implementation but subsequently stabilized,4 which could be related to the sexual health promotion and education at the PrEP services. Nevertheless, recent spikes in annual rates of acute HBV infection have been noted in North American adults, and high-risk sexual behavior was the most common risk factor for acute HBV infection in the Hepatitis B Research Network cohort.5 Of note, most of the people with acute HBV infection in this cohort were born after 1991, when the universal neonatal vaccination program was introduced in the US and Canada. Therefore, improving access to HBV testing and vaccination in preventing HBV acquisition will be imperative for high-risk populations. Although PLWH has a higher incidence of acute HBV infection, studies have found that dual-active antiretroviral agents for HIV and HBV, such as lamivudine, emtricitabine, and TFV, could reduce the risk of HBV infection by up to 90% among HBV-susceptible PLWH.6,7 The preventive effects of these dual-active antiretroviral agents have been demonstrated in different risk groups, including heterosexual men and women, MSM, and people who inject drugs. Moreover, the protection against HBV transmission conferred by combinations of dual-active antiretroviral agents (TDF plus FTC or TDF plus 3TC) was 2-fold greater than the use of single dual-active antiretroviral agents, with an HR for HBV acquisition of 0.2 for TDF/3TC or TDF/FTC and 0.4 for single dual-active antiretroviral agents. Other than the choices of ART, adherence was also crucial in achieving the protection conferred by the use of dual-active antiretroviral agents.7 On the basis of this evidence among PLWH, it is biologically plausible that TVF/FTC may provide similar protection against incident HBV infections among high-risk HIV-negative individuals. In this issue, Mizushima et al8 demonstrated in a real-world setting that TFV-based PrEP prevented incident HBV infections among HIV-negative MSM at a high risk. In this study, the serologic markers of HBV (HBsAg; HBcAb, and HBsAb) were prospectively tested every 3 months along with tests for HIV and other bacterial STIs, which could ensure a more precise and frequent detection of asymptomatic infections. Although the incidence rates of bacterial STIs among the participants were as high as 30%–50% annually, the risk of acute HBV infection was reduced by 87% among the participants who received TFV-based PrEP compared with those who did not initiate PrEP during the study period, which was similar to the preventive effect provided by combinations of dual-active antiretroviral agents among PLWH.6,7 In subanalysis, for the individuals testing positive for HBsAb and negative for HBcAb but not on PrEP, the risk of acute HBV infection was lower by 47% compared with the participants who tested negative for 3 HBV serological markers and did not receive PrEP. These findings suggest the potentially additive benefits of preventing HBV acquisition by TFV-based regimens and maintenance of seroprotection against HBV for high-risk individuals. However, there are several limitations to this prospective observational study. Although both PrEP regimens showed high effectiveness in preventing both HIV and HBV infection, the decisions of the participants to receive free-of-charge TDF/FTC or TAF/FTC in the clinical trial, to purchase TDF/FTC or TAF/FTC at their own expense, or not to initiate PrEP could be made on the eligibility criteria of the trial, personal preferences, sexual activity and perceived risks, and financial status, all of which could confound the findings observed. The insufficient number of events observed in this study precluded the investigators from conducting multivariate analysis. In addition, adherence is known to be a key factor in the efficacy of PrEP in preventing HIV (and HBV) infection; however, the adherence levels of the participants in this study were uncertain. Finally, although one of the inclusion criteria of this study was testing negative for HBsAg, HBcAb, and HBsAb, the information on HBV vaccination or revaccination among the PrEP users before or during the study period was lacking. ACIP recommended universal HBV vaccination in adults aged under 60 years and those aged over 60 years with risk factors for HBV acquisition. However, the optimal level of HBsAb in conferring protection against HBV remains to be defined for a high-risk population. In this study, the HBsAb titers for the 3 individuals not on PrEP who tested positive for HBsAb and negative for HBcAb and acquired acute HBV infection during the follow-up were 910.8, 47.0, and 98.1 mIU/mL, respectively, suggesting that more investigations are warranted to better define the seroprotective levels of HBsAb among the high-risk populations. This finding also emphasizes that, in addition to the adoption of safe sex practices, all people receiving PrEP services would receive complete serological tests to exclude chronic hepatitis B and to identify individuals for HBV vaccination9; moreover, follow-up of HBV serological markers is indicated for booster vaccination to be provided because of seroprotection may wane with time. Recently, the first approved long-acting injectable cabotegravir (CAB-LA) that is administered bimonthly has been recommended as an option for HIV prevention by the World Health Organization since 2022, and access would be expanded widely from high-income countries to middle-income or low-income countries in the near future. However, CAB-LA is not active against HBV, which has raised concerns among many experts that the use of CAB-LA for PrEP (and coformulation with rilpivirine for the treatment of HIV infection) might leave the door open to the transmission of HBV.10 Therefore, while expanding the services for HIV prevention, health care workers should perform hepatitis evaluation, provide information, education and counseling about the risk of HBV acquisition, and encourage HBV vaccination among PrEP users. Before the availability of long-acting agents with anti-HBV activity, preventing 2 viral infections with 1 tablet of medicine will continue to be an important strategy in facilitating the achievement of HBV and HIV elimination.